PD‐1 expression affects cytokine production by ILC2 and is influenced by peroxisome proliferator‐activated receptor‐γ

INTRODUCTION: Innate lymphoid cells (ILCs) can provide early cytokine help against a variety of pathogens in the lungs and gastrointestinal tract. Type 2 ILC (ILC2) are comparable to T helper 2 cells found in the adaptive immune system, which secrete cytokines such as interleukin 5 (IL-5) and IL-13 and have been found to play roles in host defense against helminth infections and in allergic responses. Recent studies have identified that programmed cell death protein 1 (PD-1) and peroxisome proliferator activated receptor-gamma (PPAR-gamma) are highly expressed by ILC2. We examined whether PD-1 plays a role in ILC2 function and whether there was any connection between PD-1 and PPAR-gamma METHODS: To ensure that only innate immune cells were present, ILC2 cells were examined from RAG1(-/-) and PD-1(-/-) xRAG1(-/-) mice under steady-state or following inoculation with IL-33. We also tested ILC2 generated from bone marrow of RAG1(-/-) and PD-1(-/-) xRAG1(-/-) mice for their production of cytokines. These in vitro-derived ILC2 were also exposed to agonist and antagonist of PPAR-gamma. RESULTS: We found that ILC2 from PD-1(-/-) xRAG1(-/-) mice had reduced frequencies of IL-5 and IL-13 producing cells both in vitro upon IL-33 stimulation and in vivo following intraperitoneal administration of IL-33 when compared with ILC2 from RAG1(-/-) mice. However, by adding IL-2, IL-25, and thymic stromal lymphopoietin to the in vitro cultures, the frequency of IL-5 and IL-13 expressing ILC2 from PD-1(-/-) xRAG1(-/-) mice became similar to the frequency observed for ILC2 from RAG1(-/-) mice. In addition, PPAR-gamma agonists and antagonists were found to increase and decrease PD-1 expression on ILC2 respectively. CONCLUSIONS: These findings illustrate that chronic loss of PD-1 plays a role in ILC2 function and PD-1 expression can be modulated by PPAR-gamma.